Toyaburgine, a Synthetic -Biphenyl-Dihydroisoquinoline Inspired by Related ,-Coupled Naphthylisoquinoline Alkaloids, with High Efficacy in Preclinical Pancreatic Cancer Models.

Pancreatic cancer is a highly aggressive and lethal malignancy, with a 5-year survival rate below 10%. Traditional chemotherapy, including gemcitabine, has limited efficacy due to chemoresistance and a unique tumor microenvironment characterized by hypovascularity and nutrient deprivation. This study reports on the discovery of a new -biphenyl-dihydroisoquinoline, named toyaburgine (), inspired by naturally occurring -coupled naphthylisoquinoline alkaloids. Developed through systematic structural optimization, toyaburgine is a potent anticancer agent, showing promise for pancreatic cancer treatment. It exhibits strong antiausterity activity with low nanomolar PC values, effectively inhibiting pancreatic cancer cell viability under nutrient-deprived conditions. , causes significant morphological changes and cancer cell death in MIA PaCa-2 cells while also inhibiting cell migration and colony formation, which indicates its antimetastatic potential. Mechanistically, toyaburgine disrupts the PI3K/Akt/mTOR pathway, essential for pancreatic cancer cell survival in a stressful microenvironment, and inhibits MIA PaCa-2 spheroid formation. , toyaburgine, alone or combined with gemcitabine, shows effective tumor suppression in subcutaneous xenograft and clinically relevant orthotopic models, where it also reduces cachexia. These results highlight the potential of toyaburgine as a new therapeutic drug for pancreatic cancer. Its combination with gemcitabine presents a promising treatment approach by targeting both proliferating and gemcitabine-resistant cancer cells.